Inhaled ambient air, on average contains about 78% nitrogen, 21% oxygen, 0.96% argon and 0.04% carbon dioxide, helium, water, and other gases. The exhaled breath contains approximately 4% to 5% more carbon dioxide and 4% to 5% less oxygen than was inhaled. Furthermore, exhaled breath contains about 5% water vapor, and some parts per million (ppm) of hydrogen, carbon monoxide, ammonia, acetone, methanol, ethanol and nitric oxide (NO).
The measured content of exhaled breath can reveal physiological information about a person, as many components of the exhaled breath are produced or altered by the cells of the lungs and the respiratory tract. The physiological information may for instance be used to diagnose pathological conditions or the effect of a particular treatment. NO is an example of a component which can be used as an indicator for inflammation.
Endothelial cells on the inner surface of blood vessels, nerve cells and inflammatory cells produce NO in the body. In the respiratory system, alveolar cells, the respiratory tract epithelium or another type of cells in contact with the lungs or the airways of the respiratory tract produce endogenous NO. This NO is secreted into the air in the respiratory ducts and/or lungs and can be measured in exhaled air.
An evaluation of the production of endogenous NO in the lungs and respiratory ducts provides a measurement of the condition and/or function of the lungs and respiratory ducts. The NO measured in the exhaled air is unlikely to emanate from other organs in the body since NO produced in other locations of the body would immediately bind to the blood's hemoglobin and then be broken down subsequently.
NO is formed endogenously along the whole breathing pathway, i.e. in the oral cavity, in the sinuses, in the nose, in the trachea past the larynx, in the bronchia and within the “free space” in the lungs, as well as in the inner blood-filled parts of the lungs. As the diagnostic purpose is directed to the condition of the lungs and/or respiratory tract, the NO generated in the volume of the mouth, nose, throat and bronchus are of less interest and should advantageously be disregarded. The volume of the mouth, nose, throat and bronchus is known as the “dead space” and is typically approximately 2 ml per kg of body weight, although certain deviations can occur with regard to physique, age, sex and the possible use of breathing aids such as tracheotomy or intubation tubing.
As the volume of the “dead space” should be disregarded there is a significant advantage from a diagnostic perspective with collecting a sample for NO measurement from the last part or portion of the exhalation. As the last part should be collected, the commencing phase is discarded by allowing a volume exceeding the volume of the “dead space” by a suitable factor to flow through the device before collecting a sample. Furthermore, it is advantageous to allow the exhalation flow from the patient to settle to a continuous flow, such that a steady level of exhaled NO is reached. The state which is sought after is known as a “plateau” of the exhalation.
The following paragraph comes from the American Thoracic Society (ATS)/European Respiratory Society (ERS) Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide, 2005, which is hereby incorporated by reference:
Online methods refer to exhalations where the expirate is continuously sampled by the NO analyzer, and the resultant NO profile versus time or exhaled volume, together with other exhalation variables (e.g., airway flow rate and/or pressure), is captured and displayed in real time. This enables the test administrator to monitor the exhalation to ensure conformation to the required flow rate and pressure parameters and the achievement of an adequate NO plateau. In the exhalation phase two factors are critical in ensuring reproducible and standardized measurements of lower respiratory tract exhaled NO: (1) exclusion of nasal NO and (2) standardization of exhalation flow rate. The exclusion of nasal NO is important in view of the high nasal NO levels relative to the lower respiratory tract. This nasal NO can enter the oral expiratory air via the posterior nasopharynx. Closure of the velopharyngeal. With biofeedback of expiratory pressure or flow rate, most subjects are able to maintain low flow rates that vary little from the desired target. In general, an exhalation is deemed adequate if the mean exhalation flow rate is 0.05 L/second (10%) during the time of the NO plateau generation, and instantaneous flow rate is not less than 0.045 L/second or greater than 0.055 L/second at any time during the exhalation. If it is not possible to keep within these values, the results should still be recorded and the failure to achieve this flow rate criterion noted in the record. The duration of exhalation must be sufficient; at least 4 seconds for children below 12 years and 6 seconds for children above 12 years and adults. This corresponds to an exhaled volume of at least 0.3 L in adults at an exhalation flow rate of 0.05 L/second to allow the airway compartment to be washed out and a reasonable plateau achieved. In general, patients can exhale comfortably up to 10 seconds, and this may be necessary for the achievement of a stable NO plateau. The plateau concentration in NO should be evaluated over a 3-second (0.15 L) window of the exhalation profile. A plateau is defined according to the following guidelines, two points, A and B, which should be chosen to define the first 3-second window in the exhaled concentration profile such that the absolute magnitude of A-B is less than 10%. The plateau concentration, FeNO, is then defined at the mean concentration over this 3-second window.
To meet the requirements of the ATS/ERS, a total of 0.15 L must be collected and analyzed during online NO measurement and a total of at least 0.3 L for an adult needs to be used to gather the 0.15 L to be measured, i.e. 0.15 L needs to be discarded.
U.S. Pat. No. 6,038,913 to Persson et al. discloses a device for collecting and separating the first exhalation volume from the “dead space” of the patient (and of the instrument) in a first chamber, whereafter the sample for measurement is collected in a different chamber having a volume of at least the required 0.15 L. The device thus takes a sample of at least 0.15 L from the plateau-region for analysis, as required by the ATS.
J. H. Green in “An introduction to human physiology”, 3rd edition, 1966, Oxford University Press, London, Chapter 5 “Respiration”, also discloses (especially in FIG. 99), the possibility to, during the exhalation, first fill an initial balloon with air from the “dead space” and a part of the alveolar air with a second balloon closed-off, and thereafter close-off the flow to the said initial balloon and collect the remaining exhaled air of the exhalation phase, which comprising the alveolar air, in a second balloon. In this case, the contents of oxygen and carbon dioxide are determined. In the filling of both these balloons, the patient breaths against a considerable resistance or back-pressure. Further, the balloon does not provide a distinct end-point determining the exhaled volume.
In the two examples of prior art devices above a chamber of 0.15 L is required for the sample collection, which creates a lower limit on the size of the device which must be considered to be a substantial design limitation.